During erythropoiesis, red blood cells are matured in fetal liver or adult bone marrow through the proliferation and differentiation of committed progenitor cells, which are the erythroid burst forming unit and the erythroid-colony forming unit. These progenitor cells are dependent upon lineage-specific growth factors for their proliferation and differentiation. In contrast, primitive pluripotent hematopoietic stem cells, which are generally quiescent and are triggered to proliferate only when a need is expressed in the periphery, respond to a combination of multiple hematopoietic growth factors. Recently, several factors have been identified that appear to be involved in the triggering of cell division in the quiescent hematopoietic progenitor cells and in the differentiation of committed progenitor cells. It has been demonstrated that burst promoting factor (BPF), colony stimulating factor (CSF), and interleukin-3 (IL-3) have a dependent-effect upon the proliferation and differentiation of pluripotent stem cells and progenitor cells. Additional studies have also determined that erythropoietin (EPO) is the sole factor involved in the late stages of erythroid differentiation prior to the stage of basophilic erythroblast. However, the role of these factors in the regulation of the final differentiation stages, beyond basophilic eythroblast, are still uncertain.
Numerous types of cells express cell-surface proteins known as "integrins" which are recognized by extracellular proteins such as fibronectin, collagen, osteoprotein, fibrinogen, vitronectin, thrombospondin, and Von Willebrand factor (VWF), which function in the attachment of these cells to their surroundings. Integrins, which act as receptors for several of these aforementioned extracellular proteins, have been identified with human platelet glycoprotein--which functions to mediate VWF-dependent adhesion of platelets to exposed vascular endothelium.
Another common group of adhesion-promoting molecules are referred to generically as "cellular adhesion molecules" (CAMs) which are glycosylated proteins belonging to the immunoglobulin super-family. The classified CAMs include: neuronal cellular adhesion molecule (NCAM); myelin-associated glycoprotein (MAG); intercellular adhesion molecule (ICAM); lymphocyte function-associated antigen-3 (LFA-3); the T-cell subset cell-surface marker CD-4; the major glycoprotein of peripheral myelin (Po); carcinoembryonic antigen (CEA); and platelet-endothelial cell adhesion molecule 1 (PECAM-1). See e.g., Williams, D. F. & Barclay, T., 6 Ann. Rev. Immunol. 381 (1988).
Of particular interest in the instant invention, is platelet-endothelial cell adhesion molecule 1 (PECAM-1). These cellular adhesion molecules typically are comprised of 711 amino acids and possess a molecular weight of 130 kd. PECAM-1 has been demonstrated to be expressed on platelets, circulating monocytes, and at the intercellular junctions of resting endothelial cells. See e.g., Ashman & Aylett, 38 Tissue Antigen 208 (1991). PECAM-1's are important mediators of platelet-platelet, platelet-leukocyte, and platelet-endothelial cell interactions in the process of platelet aggregation. In addition, these molecules may also be involved in the development of atherosclerotic plaque and thrombi from vascular trauma (e.g., from angioplasty), as well as in leukocyte-endothelial cell interactions in inflammation and transendothelial cell migration.